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Introduction: Physical activity (PA) is known to be effective in treating and preventing many lifestyle diseases including CVD, stroke, depression, type II diabetes, Alzheimer’s disease, as well as breast and colon cancer. To date the direct medical cost-savings of PA as a medical intervention are poorly understood.Hypothesis: We hypothesized that a 10% increase in the proportion of US citizens who meet the minimum weekly exercise requirements of 150 minutes per week would lead to savings in direct medical costs (DMC) and cases prevented, as related to the above diseases.Methods: Population Attributable Risk (PAR) was calculated as PAR= (1+Prf x (RR-1))/(Prf x(RR-1)), where Prf is the percentage of the U.S. population not meeting minimum exercise requirements and RR is the relative risk of disease for sedentary versus physically active individuals. Prf and RR data were retrieved from the most recent and comprehensive meta-analyses and systematic reviews. PAR was calculated for each disease under two conditions; first, Prf was equal to the current percent (9.6%) of the population estimated to achieve the minimum weekly PA requirements. Second, Prf was equal to the initial Prf plus 10 percent (19.6%). For each condition the following were calculated: Attributable DMC=(PAR x DMC), preventable cases=(PAR x Prevalence) and Savings=(Condition 2- Condition 1).Results: The Prevalence, RR, PAR and DMC are provided in Table 1. This table also describes the potential savings in DMC and new cases by improving the Prf by 10%. A 10% increase in US citizens who meet the minimum weekly exercise requirements could lead to a total savings of 10.78 billion USD in DMC and 2.1 million cases prevented related to the studied diseases.Conclusion: A healthcare system directed PA intervention that effectively leads to a 10% increase in US citizens that meet minimum weekly exercise requirements and costs less than 10.78 billion dollars has the potential to be cost-effective, and prevent and treat, millions of cases in the United States.